Factor Xa and Factor Xa assembled in the prothrombinase complex (Factor Xa, Factor Va, calcium and phospholipid) activate prothrombin (Factor II) to generate thrombin (Factor IIa). Factor Xa is strategically located at the intersection of extrinsic and intrinsic pathways of the blood coagulation system. Thus, an inhibitor of Factor Xa inhibits the formation of thrombin and, therefore, is useful for preventing or treating disorders related to blood coagulation in mammals.
Anticoagulant therapy is indicated for the treatment and prophylaxis of a variety of thrombotic conditions of both the venous and arterial vasculature. In the arterial system, abnormal thrombus formation is primarily associated with arteries of the coronary, cerebral and peripheral vasculature. The diseases associated with thrombotic occlusion of these vessels principally include acute myocardial infarction (AMI), unstable angina, thromboembolism, acute vessel closure associated with thrombolytic therapy and percutaneous transluminal coronary angioplasty (PTCA), transient ischemic attacks, stroke, intermittent claudication and bypass grafting (CABG) of the coronary or peripheral arteries. Chronic anticoagulant therapy may also be beneficial in preventing the vessel luminal narrowing (restenosis) that often occurs following PTCA and CABG, and in the maintenance of vascular access patency in long-term hemodialysis patients. With respect to the venous vasculature, pathologic thrombus formation frequently occurs in the veins of the lower extremities following abdominal, knee and hip surgery (deep vein thrombosis, DVT). DVT further predisposes the patient to a higher risk of pulmonary thromboembolism. A systemic, disseminated intravascular coagulopathy (DIC) commonly occurs in both vascular systems during septic shock, certain viral infections and cancer. This condition is characterized by a rapid consumption of coagulation factors and their plasma inhibitors resulting in the formation of life-threatening clots throughout the microvasculature of several organ systems.
In addition to their use in anticoagulant therapy, Factor Xa inhibitors are useful in the treatment or prevention of other diseases in which the generation of thrombin has been implicated as playing a physiologic role. For example, thrombin has been proposed to contribute to the morbidity and mortality of such chronic and degenerative diseases as arthritis, cancer, atherosclerosis and Alzheimer's disease by virtue of its ability to regulate many different cell types through specific cleavage and activation of a cell surface thrombin receptor, mitogenic effects, diverse cellular functions such as cell proliferation, for example, abnormal proliferation of vascular cells resulting in restenosis or angiogenesis, release of PDGF and DNA syntheses. Inhibition of Factor Xa will effectively block thrombin generation and therefore neutralize any physiologic effects of thrombin on various cell types.
The representative indications discussed above include some, but not all, of the possible clinical situations amenable to treatment with a Factor Xa inhibitor.
Oxoazaheterocyclyl Factor Xa inhibitors are disclosed in International Patent Application Numbers PCT/US98/07158, published Oct. 22, 1998; PCT/US98/07159, published Oct. 22, 1998; PCT/US98/07160, published Oct. 22, 1998; PCT/US98/07161, published Oct. 22, 1998; and PCT/US96/09290, published Dec. 19, 1996. Oxoazaheterocyclyl fibrinogen antagonists are disclosed in International Patent Application Number PCT/US92/09467, published May 13, 1993.
Vascular injury, caused by biochemical or physical perturbations, results in the activation of the coagulation system, culminating in the generation of thrombin. Thrombin promotes thrombus formation by catalyzing the transformation of fibrinogen to fibrin, by activating Coagulation Factor XIII, which stabilizes the thrombus, and by activating platelets. Thrombin promotes further thrombus growth by positive feedback to the coagulation cascade (activation of Coagulation Factors V and VIII), resulting in the explosive production of thrombin. Thrombin is present, and active, in the thrombi of patients with thrombotic vascular disease. Thrombin inhibition prevents the action of thrombin after thrombin has been activated from prothrombin. An inhibitor of thrombin inhibits cleavage of fibrinogen to fibrin, activation of Factor XIIIa, activation of platelets, and feedback of thrombin to the coagulation cascade to generate more thrombin. Consequently, inhibition of thrombin activity with a direct thrombin inhibitor would be useful for preventing or treating disorders related to blood coagulation in mammals.
The combined inhibitors of Factor Xa and Factor IIa described herein inhibit thrombin activity (via IIa inhibition) and thrombin production (via Factor Xa inhibition). Therefore, these agents inhibit any thrombin that may be present and also inhibit the further production of thrombin. Other agents which have this dual activity include heparin and low molecular weight heparins (LMWHs), which have demonstrated efficacy in thrombotic diseases. However, heparin and LMWHs act indirectly through a cofactor, antithrombin-III (ATIII), to inhibit Xa and IIa. The heparin/ATIII complex is too large, however, to inhibit thrombus-bound Xa and IIa, thus limiting its efficacy. Direct inhibitors of Factor Xa and Factor IIa, as described herein, are capable of inhibiting soluble and thrombus-bound Xa and IIa, thus providing an important therapeutic advantage over currently available Xa/IIa inhibitors.